This invention relates to a sodium-hydrogen exchanger type 1 (NHE-1) inhibitor.
Myocardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and can reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these surgical settings (perioperatively). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction-and dysfunction in patients “at risk” (such as greater than 65 years, exercise intolerant, coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery.
The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood.
A variety of publications have disclosed the use of guanidine derivatives as useful for the treatment of, for example, arrhythmias.
A recent published patent application, PCT/IB99/00206 published as WO 99/43663 on Sep. 2, 1999, the disclosure of which is hereby incorporated by reference, discloses a variety of NHE-1 inhibitors including [5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine. The publication further states that “preferred salts of the immediately preceding compound are the mono- or di-mesylate salts.” One group of preferred compounds, which include hydroxyquinoline compounds, is described in claim 102 of the published application. Of course, some of these hydroxyquinoline compounds can exist in several tautomeric forms such as the quinolone form as described in that patent application. In addition, commonly assigned U.S. provisional application Ser. No. 60/162,374 was filed on Oct. 29, 1999 and is directed to crystal forms of the above described NHE-1 inhibitor.
PCT/JP97/04650 application published on Jun. 25, 1998 discloses N-[(substituted five-membered heteroaryl)]guanidine compounds to be useful as inhibitors of Na+/H+ exchange and consequently effective for the treatment of various diseases such as hypertension, arrhythmia, angina pectoris, myocardial infarct, arteriosclerosis, and complications of diabetes.
Thus, there is clearly a need and a continuing search in this field of art for compounds for the treatment of perioperative myocardial ischemia.